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Functional Similarity and Differences Between Selection-Independent CD4^-CD8^- T Cells and Positively Selected CD8 T Cells Expressing the Same TCR and the Induction of Anergy in CD4^-CD8^- T Cells in Antigen-Expressing Mice¹

Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

In TCR- transgenic mice, CD4^-CD8^- TCR-⁺ ( DN) cells arise in the absence of positively selecting MHC molecules and are resistant to clonal deletion in Ag-expressing mice. In this study the activation requirements and functional properties of double-negative (DN) cells were compared with those of positively selected CD8⁺ cells expressing equivalent levels of the same MHC class I-restricted transgenic TCR. We found that positively selected CD8⁺ cells required a lower density of the antigenic ligand for optimal proliferative responses compared with DN cells derived from nonpositively selecting mice. However, when the CD8 coreceptor on CD8⁺ cells was blocked with an anti-CD8 mAb, both DN and CD8⁺ cells exhibited the same dose-response curve to the antigenic ligand and the same dependence on CD28/B7 costimulation. Positively selected CD8⁺ cells also differed from DN cells in that they differentiated into more efficient killers and IL-2 producers after Ag stimulation, even after CD8 blockade. However, Ag-activated DN and CD8⁺ cells were equally efficient in producing IFN-, suggesting that this functional property is independent of positive selection. We also found that DN cells recovered from the lymph nodes of Ag-expressing mice were functionally anergic. This anergic state was associated with defective proliferation and IL-2 production in response to Ag stimulation. These observations indicate that DN cells can be anergized in vivo by physiological levels of the antigenic ligand.

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